The αvβ8 integrin is a key activator of transforming growth factor β(TGFβ), which has been shown to inhibit anti-tumor immunity. Previous work has suggested that αvβ8 on tumor cells could modulate tumor growth and responses to immune checkpoint blockade. We now show that a potent blocking monoclonal antibody against avb8 (ADWA-11) causes growth suppression or complete regression in syngeneic models of squamous cell carcinoma (CCK168), mammary cancer (EMT-6), colon cancer (CT26), and prostate cancer (TRAMPC2), especially when it is combined with other immunomodulators (anti-PD-1, anti-CTLA-4 or 4-1BB) or radiotherapy. αvβ8 is expressed on tumor cells in some of these models, but tumor cell expression of avb8 is not essential for the beneficial effects of ADWA-11 therapy. αvβ8 is consistently expressed at highest levels on CD4+CD25+ T cells within tumors, and specific deletion of Itgb8 from T cells is as effective as ADWA-11 in suppressing tumor growth. Treatment with ADWA-11 increases expression of a suite of genes in tumor infiltrating CD8+ T cells that are normally inhibited by TGFβ and are involved in tumor cell killing, including Granzyme B and Interferon-g. These findings solidify αvβ8 integrin as a promising target for cancer immunotherapy, even for tumors that do not express this integrin.
Dodagatta-Marri, Eswari and Ma, Hsiao-Yen and Liang, Benjia and Li, John and Meyer, Dominique S. and Sun, Kai-Hui and Ren, Xin and Zivak, Bahar and Rosenblum, Michael D. and Headley, Mark B. and Pinzas, Lauren and Reed, Nilgun I. and Del Cid, Joselyn S. and Adoumie, Maeva and Hann, Byron C. and Yang, Sharon and Giddabasappa, Anand and Noorbehesht, Kavon and Yang, Bing and Dal Porto, Joseph and Tsukui, Tatsuya and Niessen, Kyle and Atakilit, Amha and Akhurst, Rosemary and Sheppard, Dean, Integrin αvβ8 on T Cells is Responsible for Suppression of Anti-Tumor Immunity in Syngeneic Models and is a Promising Target for Tumor Immunotherapy. Available at SSRN: https://ssrn.com/abstract=3588885 or http://dx.doi.org/10.2139/ssrn.3588885
This version of the paper has not been formally peer reviewed.
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